This project is a comprehensive, multidisciplinary effort to understand the natural history and modes of transmission of viruses and other infectious agents that are associated with cancer. With numerous intramural and extramural laboratory, clinical, and epidemiologic collaborators, and a core of prospective cohort and case-control studies, the effort is focused on human immunodeficiency virus (HIV), hepatitis C virus (HCV), and Kaposi's sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8 or HHV-8). In our large Multicenter Hemophilia Cohort Study (MHCS), longitudinal patterns of HIV viral load among hemophilic children were found to resemble those previously noted in adults. Hemophilic participants who had escaped HIV infection, despite susceptible (wild-type) chemokine receptor geneotypes and intensive HIV exposure, were found to have diminished immune responses, suggesting that immune activation may be required for establishment of HIV infection. Polymorphisms in three more genes (CX3CR1, IL10, and HLA*B35-Px) were found to affect the rate of HIV progression to AIDS. Injection drug users were found to have markedly increased mortality due to HIV and to drug overdose but not to infection with the transforming human retrovirus, HTLV-II. MHCS participants and injection drug users with HCV infection were found to have a higher risk of progression to end-stage liver disease (ESLD) with particular HLA class II alleles. ESLD risk among MHCS participants with both HIV and HCV infections was related to atypical antibody patterns against HCV. A Second Multicenter Hemophilia Cohort Study (MHCS-II) was launched to improve understanding of HCV natural history. New antibody assays for the diagnosis of KSHV infection were developed, and an enzyme immunoassay against the KSHV K8.1 recombinant protein was found to have high sensitivity and specificity in African and Maltese populations. In the elderly populations of three Mediterranean islands known to be endemic for Kaposi's sarcoma, KSHV seroprevalence and risk of Kaposi's sarcoma were quantified. A case-control study to identify risk factors for classical (non-AIDS) Kaposi's sarcoma is in progress. In a case-control study of childhood leukemia, antibody seroprevalence against Haemophilus influenzae type b was found to be reduced among cases under age 6 and increased among older cases. This supports the hypothesis that a delay in the timing of early childhood infections (or other antigenic challenges) increases the risk of leukemia.